Process of preparing 4-hydroxy-3-keto-4-androstenes



F Patented 7 2,999,870 As far as is known, there are substantially three proc- PROCESS OF PREPARING esses for the manufacture of 4-hydroxy-3-keto-4-andro- KETO-4-ANDROSTENES stenes (IV) from the corresponding 3-keto-4-androstenes Brill") f Remit? d lli, and Bianca Patelli, all (I). They are illustrated in the reaction scheme below,

of M1lan, Italy, assignors to Socreta Farmaceutici 5 and are described as f ll Italia, a corporation of Italy N Drawing Filed 23, 1961Sen 92,175 1) By dehydration with acids (such as p.toluene-sul- Cl i priority, li ti It l Man 1, 19 0 fomc acid or hydrochloric acid) of the 4,5-dihydroxy-3- '10 Claims. (Cl. 260-397.4) keto-androstanes (111), which are obtained from the cor- 10 responding 3-keto-4-androstenes (I), by dihydroxylation The mvenuon relates to PrJceSS of PrePanng Y in 4,5-positions with osmium tetraoxide and hydrogen droxy-3-keto-4-androstenes from the corresponding peroxide (H. Levy et 21.; U.S.P. 2,762,818). Puyikefirgndmstanw It especlauy relates to f (2) By isomerization with acids, such as sulfuric acid manufacture of 4'hydmxy'3'keto'ii'androstenes havmg in acetic acid or boron trifluoride, of the 4,5-epoxy-3- the general fmmfla keto-androstanes (11 which are obtained with alkaline hydrogen peroxide (B. Camerino et al.: J.A.C.S. 78, 1956,

p. 3540 and U.S.P. 2,842,571).

(3) By a synthesis which comprises the dibromination x in 2,6-posin'ons of the 3-keto-4-androstenes (I) to yield the 2,6-dibromo- 3-keto-androstenes (V), from which the 4-keto-3-acyloxy-2,5-androstadienes (VI) are obtained by dehydrobromination, which by hydrogenation of the double bonds A and A (VIII), followed by hydrolysis of H the acyloxy group in 3-position (VIII), and final oxidation with Bi O are transformed into 4-hydroxy-3-keto- 4-androstenes (IV) (P. L. Iulian et al.: U.S.P. 2,900,399).

X=H or CH R=aH, H or CH3, 50K The said reaction scheme 1s as follows.

wherein B I Dehydrobromination Hydrogen Hydrolysis A A B A B A B O oniooox AC0 I/Pd) AGO V 1111003 Ho i II 0 P W vrr vrrr Dlhydroxylation (0504-13 03) Oxidation I Epox'ldatlon Hydration Dehydration A B A B A B H;OrNaOH (H S Or-MeOH) g (acid) V I h V V g Deh dration i 1' i M 5 0H i V Y 0H (a1kall) Y I 11 III IV f..f. T

i v .7 r

I BeactionwithHzSOrinAeOH i 5 v l r Reaction with BFa E l I Reaction with alkali It is known that a number of the aforesaid steps, such 3 1 as the bromination with bromine, the catalytic hydro- The prfducts of f i i F9 are P They genation, the dehydrobromination and the use of OsO; are especially useful in therapy, owing to their hormonal and BPS are undesirable from an industrial point of View. propertiessom fth Substances a also use because they areexpensive and/or dangerous, and/or;

as intermdiates in the manufacture of the corresponding cause they give P Y Q ti a b t h Besides, B. Carnerino' et al. have recently disclosed ester whlch have the same hormonal ac vly u ave that the preparatlon of 4-hydroxy derivatives of 170:-

a Prolonged-effect 4'hydmxy'tesmstemnes the cone methyl-testosterone and 17u-methyl-19-nortestosterone by sponding esters and their 116111101191 Properties have b isomerization of the corresponding 4,5-epoxy-3-keto-" described by H. Levy et al. (U.S.P."2,762,8l8). steroids with acids is impossible because such conditions cause the simultaneous removal of the hydroxy group in- The chemical and therapeutic characteristics of the 4- 17 Posifion l1ydroxy-19-nortestosterone and its esters are described Overcoming these dim lti Camerino aL in Belgian Patent 552,153. p I v ceeded in preparing said deriyatives of fi-hydroxy-lht- V 3 methyl-androstane by hydration, with diluted sulfuric acid in methanol, of the 4,5-epoxy-3-keto-androstanes (II) to yield the 4,5-dihydroxy-derivatives (III), from which the 4-hydroxy-3-keto-derivatives (IV) have been obtained by dehydration with alkali.

The process of the instant invention permits the direct manufacture of 4-hydroxy-3-keto-androstenes (IV); including the Nor-methyl analogues, from the corresponding 4,5-epoxy-steroids by reaction with suitable inorganic and/or organic bases, particularly under special experimental conditions.

The transformation of the 4,5-epoxy-3-keto androstanes (II) to 4-hydroxy-3-keto-4-androstenes (IV) by the invention is a new and very useful procesibecause it results in the manufacture of said therapeutically useful products With good yields (50-80%) by a simple and cheap step.

According to the invention, a 4-hydroxy-3 keto-4- androstene is prepared by treating the corresponding 4,5- epoxy-3-keto-androstane, dissolved in an organic solvent, preferably a tertiary aliphatic alcohol such as t.butanol or t.pentanl,-With an aqueous solution of an alkali metal hydroxide and/ or a quaternary ammonium hydroxide; at from 50 C. to 150 C., preferably from 70 C. to 100 C. for from 0.5 to hours, preferably from 1 to 2 hours,-

the employed molecular ratio of hydroxide to steroid being from 0.5 to 30, preferably from 5 to 15.

Sodium hydroxide and potassium hydroxy 17 methyl-testosterone and 4 hydroxy 17 ocmethyl-l9-nortestosterone, have been prepared, but also other 4-hydroxy-3-keto-4-androstenes having ketonic groups and/or hydroxy groups and/or alkyl groups in other positions of the steroid nucleus.

The following examples are set forth by way of illustration:

EXAMPLE 1 W 4-hydroxy-17a-methyl-testosterone (method employing potassium hydroxide) a The starting material, 4,i-epoxy-lh-metliyl androstane-l7 S-ol-3-one, is prepared by ep ox idation -with alkaline hydrogen peroxide of the 17a-methyl-t estosterone according to the general procedure described? by B.

hydroxide" may be" usedas the alkali metal hydroxides. Tetram'ethylamrnonh um hydroxide, tetraethylammonium hydroxide, pheny1-' trimethylammonium hydroxide, methylethylpiperidinium Camerino et al. in I.A.C.S. 7 1956, page e541. s a:

cifically, 10 g. of 17a-methyl-testosteronedissolved ili 500 'ml. of methanol are epoxidized inthe 4,5-position with 20 ml. of aqueous 4 N sodium hydroxide mid -34 m1. of aqueous 34% hydrogen peroxide for 3 hours at 0 C. 0.5 g. of crude 4,5-epoxy-l7oc-methyl-androstane-175- ol-3-onedissolved in 20 ml. of t.butanol are isomerizedin the presenecof 0.5 g. of pota's'sium'hydroxidedissolved in 0.5 ml. of Water, at the boiling. point for twg hours.

The solution is then cooled, neutralized with 0.5 ml. of

carbonate and finally with water to neutrality. After evaporation of the solvent a residue of 0.5 g. remains.

By recrystallization from methanol or by chromatography on Florisil (registered trademark), followed by crystallization of the fractions diluted with benzol-ether (14:1), 4-hydroxy-17u-methyl-test0sterone is obtained. M.P.=168-170 0.; at 277 mp (=12,800).

EXAMPLE 2 4-hydr0xy-17amelhyl-zestosterohe (method employing tetraethylammonium hydroxide) 0.5 g. of crude 4,5-epoxy-l'la methyl androstauerflfiol-3-one, dissolved in 20ml. of t.butanol are isomeri zed in the presence of 8 ml. of an aqueous 25% tetraethylammonium hydroxide for 2 hours at the boiling point. The process is further continued or carried out as described in Example 1, to yield 4-hydroxy-l7u-methyltestosterone. H

EXAMPLE 3 4-hydroxy-17a-methyl-testosterone (method employing phenyltrimethylammonium hydroxide) 0.5 g. of crude 4,5-epoxy-17a-methyl-androstane-17B- ol-3-one, dissolved in 20 ml. of t.butanol are isomerized in the presence of 3.5 g. of phenyltrimethylammonium hydroxide dissolved in 15 ml. of water for 1 hour at the boiling point. The remainder of the process is carried out as described in Example 1; to yield 4-hyd10XY-17ozmethyl-testosterone.

M.P.=168170 0.; A at 277 m (e=12,6

EXAMPLE 4 4-hydroxy-17u-methyl-testosterone (method employing methylethylpiperidinium hydroxide) By operating as described in Examplei3, but using methylethylpiperidinium hydroxide instead of phenyltrimethylammonium hydroxide; 4-hydroxy 17 d methyl testosterone is obtained.

M.P. 168-170 0.; A at 278 mu (e=12,850).

EXAMPLE 5 4-hydroxy-17a-methyl-testosterone (method employing benzyltrimethylammonium hydroxide) By operating as described in Example 3 but using benzyl-trimethylammonium hydroxide instead of phenyltrimethylammonium hydroxide, 4-hydroxy-l7u-methyltestosteroneis obtained;

M.P. 168-170 C.; A at 278 my." (e=12,990).

EXAMPLE 6 4-hydroxy-testosterone 1 g. of crude 4,5-epoxy-androstane-1713-ol-3-one (prepared as described by B. Camerino et al. in J.A.C.S. 78, 1956, page 3540), dissolved in 40 ml. of t.butanol are isomerized in the presence of 16 ml. of aqueous 25% tetraethylammonium hydroxide for 2 hours at the boiling point. The remainder of the process is carried out as described'in Example 1, and 4-hydroxy-testosterone is obtained.

M.P. 221-223 6.; 7 at 278 mp. (e=11,9 2,0).

EXAMPLE 7' 4-hydroxy-1Q-nortesrOsterone' By operating as described in Example 6, but using crude 4,5-epoxy-19-nor-androstane-l7B-ol-3-one instead of crude 4,5-epoxy-androstane-l7fl-ol 3-one, 4-hydroxy- 19-nortestosterone is obtained;

M.P. 188-19 0.; A at 278 m 11,680).

The said crude 4,5-epoxy 19-nor-androstane-17 3-01-3- one'is prepared as described in Examplel of Camerino application Serial No. 618,442 filed October 26, 1956. Namely, 1.9 grams of l9-nortestosterone are dissolyed in cc. methanol and treated forone hour with 3.8

cc. 4/N NaOH and 7 cc. 36% H The solution is then acidified with 0.4 cc. acetic acid, diluted with water and extracted with ethylacetate. The extract is washed with water, dried, and distilled.

EXAMPLE 8 4-hydroxy-17a-methyl-19-nortestosterone Upon operating as described in Example 6, but using crude 4,5-epoxy-l7a-methyl-19-nor-androstane-17,8-01-3- one (prepared by epoxidation of g. of 17a-methyl-19- nortestosterone dissolved in 600 ml. of methanol in the presence of 20 m1. of aqueous 4 N sodium hydroxide and 34 ml. of aqueous 34% hydrogen peroxide for 1 hour at 0 C.) instead of crude 4,5-epoxy-androstane- 17B-ol-3-one, 4-hydroxy-17a-methyl-19-nortestosterone is obtained.

M.P.=168-170 0.; k at 277 m (e=12,850).

EXAMPLE 9 4,11p-dihydroxy-1 7 a-m ethyl-testosterone Upon operating as described in Example 6, but using crude 4,5 epoxy-lh-methyl-androstane-l15,17p-dio1-3- one (prepared by epoxidation of 10 g. of llfl-hydroxy- 17cc-methYl-t6StOSt61'Ol1G dissolved in 600 ml. of methanol in the presence of 20 ml. of aqueous 4 N sodium hydroxide and 34 ml. of aqueous 34% hydrogen peroxide for 3 hours at 0 C.) instead of crude 4,5-epoxy-andro stane-17 8-ol-3-one, 4,1lfl-dihydroxy-l7a-methy1-testosterone is obtained.

M.P.=183-185 0.; A at 278 m (e=12,250).

We claim:

1. A process of preparing a 4-hydroxy-3-keto-4-androstene which comprises treating the corresponding 4,5- epoxy-3-keto-androstane, dissolved in an organic solvent, with an aqueous solution of a base taken fi'om the group consisting of alkali metal hydroxides and quaternary ammonium hydroxides, at from 50 C. to 150 C.

2. The process of claim 1, the solvent being tertiary butanol.

3. The process of claim 1, the solvent being tertiary pentanol.

4. The process of claim 1, the androstene prepared being a compound of the group consisting of 4-hydroxy- 17alpha-methyl-testosterone; 4-hydroxy-testosterone; 4-hy- 6 droxy-l9-nortestosterone; 4-hydroxy-17alpha-methyl-19- nortestosterone; and 4,1lbeta-d-ihydroxy-17alpha-methyltestosterone.

5. A process of preparing a 4-hydroxy-3-keto-4-androstene which comprises treating the corresponding 4,5- epoxy-3-keto-androstane, dissolved in a liquid solvent of the latter, comprising a tertiary aliphatic alcohol, with an aqueous solution of a base taken from the group consisting of alkali metal hydroxides and quaternary ammonium hydroxides, at from C. to C., the molecular ratio of hydroxide to steroid being from 5 to 15 of the hydroxide to 1 of the steroid.

6. A process of preparing 4-hydroxy-17alpha-methyltestosterone comprising treating 4,5-epoxy-17alpha-methyl-androstane-17beta-ol-3-one dissolved in an organic solvent with an aqueous solution of a base taken from the group consisting of alkali metal hydroxides and quaternary ammonium hydroxides at from 50 to C.

7. A process of preparing 4-hydroxy-testosterone comprising treating 4,5-epoxy-androstane-17beta-ol-3-one, dissolved in an organic solvent, with an aqueous solution of a base taken from the group consisting of alkali metal hydroxides and quaternary ammonium hydroxides at from 50 to 150 C.

8. A process of preparing 4-hydroxy-19-nortestosterone, comprising treating 4,5-epoxy-19-nor-androstane-17betaol-3-one, dissolved in an organic solvent, with an aqueous solution of a base taken from the group consisting of alkali metal hydroxides and quaternary ammonium hydroxides at from 50 to 150 C.

9. A process of preparing 4-hydroxy-17alpha-methyll9-nortestosterone, comprising treating 4,5-epoxy-17alphamethyl-17-nor-androstane-17beta-ol-3-one, dissolved in an organic solvent, with an aqueous solution of a base taken from the group consisting of alkali metal hydroxides and quaternary ammonium hydroxides at from 50 to 150 C.

10. A process of preparing 4,11beta-dihydroxy-17- alpha-methyl-testosterone, comprising treating 4,5-epoxy- 17alpha-methyl-androstane-11beta,17beta-diol-3-one dissolved in an organic solvent, with an aqueous solution of a base taken from the group consisting of alkali metal hydroxides and quaternary ammonium hydroxides at from 50 to 150 C.

No references cited. 

1. A PROCESS OF PREPARING A 4-HYDROXY-3-KETO-4-ANDROSTENE WHICH COMPRISES TREATING THE CORRESPONDING 4,5EPOXY-3-KETO-ANDROSTANE, DISSOVED IN AN ORGANIC SOLVENT, WITH AN AQUEOUS SOLUTION OF A BASE TAKEN FROM THE GROUP CONSISTING OF ALKALI METAL HYDROXIDES AND QUATERNARY AMMONIUM HYDROXIDES, AT FROM 50*C. TO 150*C. 